The compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole with a chiral carbon at the 6 position and that exists as a pair of optical enantiomers depending on whether the 6-propylamino group is in the S(−) or R(+) orientation. The S(−) enantiomer, (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (PPX), commonly known by its USAN name, pramipexole, and commercially available as the dihydrochloride salt as Mirapex®, is a potent dopamine agonist, and thus, mimics the effects of the neurotransmitter dopamine. Therefore, pramipexole is indicated for treating Parkinson's disease, cluster headaches, restless legs syndrome and bipolar disorder with only small daily doses required and tolerated by patients activates. While pramipexole is clinically effective as a dopamine agonist, the R(+) enantiomer, (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (RPPX), has greatly reduced affinity for dopamine receptors and is not a clinically useful dopamine agonist. Both enantiomers, however, have been shown to exert neuroprotective activity that is independent of dopamine receptor interaction. Each is able to confer clinical neuroprotection in patients by accumulating in the cells of the brain and the spinal cord and, more specifically, in the mitochondria of these cells where they exert a dopamine independent effect on neurological function, presumably through inhibition of lipid peroxidation, normalization of mitochondrial metabolism and/or detoxification of oxygen radicals. As such, these compounds may have utility as inhibitors of the cell death cascades and loss of cell viability observed in neurodegenerative diseases.
Neuroprotective properties of PPX have been recognized as potentially useful for the treatment of neurodegenerative disorders, but clinical experience with the drug for treatment of dopamine deficiency disorders, such as PD, have shown that dosing is limited both temporally, by the need for prolonged dose titration, and absolutely, in terms of maximum tolerated dose (MTD), due to dopamine agonist-related side effects. These dosing limitations are typical for dopamine receptor agonists of this class.
The maximum allowable single starting dose for Mirapex® (an immediate release composition) is 0.125 mg, given three times a day (t.i.d.); and the maximum allowable dose for Mirapex is 1.5 mg t.i.d., providing a maximum daily dose of 4.5 mg of Mirapex® after 7-8 weeks of titration.
While these dose levels of Mirapex® are useful for treatment of the signs and symptoms of PD and RLS, in neuroprotective assays the potency of PPX as a neuroprotective is approximately 1000-fold lower than its potency as a dopamine agonist. This suggests the therapeutically useful neuroprotective doses cannot be reached using this enantiomer.
RPPX possesses similar neuroprotective potency, but lower affinity for dopamine receptors. Accordingly, it has been advanced as a potentially more useful compound for treatment of neurodegenerative disorders. However, previously reported dopamine receptor affinity difference for the RPPX compared to PPX would still impose clinically important dose limitations and would still require dose-titration and dose-limitations to avoid dopamine-related side effects. In previous reports utilizing RPPX in (ALS), dosing of RPPX was suggested to be limited and to require significant dose-titration in animal experiments. The assumed requirement for dose-titration—specifically, the requirement to start dosing at very low doses and increase the dose to a final therapeutically effective dose level over 7-8 weeks—severely limits the usefulness of the neuroprotective potential of the RPPX enantiomer Additionally, the assumed MTD would severely limit the timely exploitation of the neuroprotective potential of the RPPX enantiomer for both acute and chronic neurodegenerative disorders.